Arehart Eric, Stitham Jeremiah, Asselbergs Folkert W, Douville Karen, MacKenzie Todd, Fetalvero Kristina M, Gleim Scott, Kasza Zsolt, Rao Yamini, Martel Laurie, Segel Sharon, Robb John, Kaplan Aaron, Simons Michael, Powell Richard J, Moore Jason H, Rimm Eric B, Martin Kathleen A, Hwa John
Department of Pharmacology & Toxicology, Dartmouth-Hitchcock Medical Center, Hanover, NH 03755, USA.
Circ Res. 2008 Apr 25;102(8):986-93. doi: 10.1161/CIRCRESAHA.107.165936. Epub 2008 Mar 6.
Recent increased adverse cardiovascular events observed with selective cyclooxygenase-2 inhibition led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra), but the mechanisms underlying these atherothrombotic events remain unclear. Prostacyclin is the major end product of cyclooxygenase-2 in vascular endothelium. Using a naturally occurring mutation in the prostacyclin receptor, we report for the first time that a deficiency in prostacyclin signaling through its G protein-coupled receptor contributes to atherothrombosis in human patients. We report that a prostacyclin receptor variant (R212C) is defective in adenylyl cyclase activation in both patient blood and in an in vitro COS-1 overexpression system. This promotes increased platelet aggregation, a hallmark of atherothrombosis. Our analysis of patients in 3 separate white cohorts reveals that this dysfunctional receptor is not likely an initiating factor in cardiovascular disease but that it accelerates the course of disease in those patients with the greatest risk factors. R212C was associated with cardiovascular disease only in the high cardiovascular risk cohort (n=980), with no association in the low-risk cohort (n=2293). In those at highest cardiovascular risk, both disease severity and adverse cardiovascular events were significantly increased with R212C when compared with age- and risk factor-matched normal allele patients. We conclude that for haploinsufficient mutants, such as the R212C, the enhanced atherothrombotic phenotype is likely dependent on the presence of existing atherosclerosis or injury (high risk factors), analogous to what has been observed in the cyclooxygenase-2 inhibition studies or prostacyclin receptor knockout mice studies. Combining both biochemical and clinical approaches, we conclude that diminished prostacyclin receptor signaling may contribute, in part, to the underlying adverse cardiovascular outcomes observed with cyclooxygenase-2 inhibition.
近期观察到选择性环氧化酶-2抑制剂会增加不良心血管事件，导致罗非昔布（万络）和伐地昔布（倍乐信）撤市，但这些动脉粥样硬化血栓形成事件背后的机制仍不清楚。前列环素是血管内皮中环氧化酶-2的主要终产物。利用前列环素受体的一种自然发生的突变，我们首次报告，通过其G蛋白偶联受体的前列环素信号传导缺陷会导致人类患者发生动脉粥样硬化血栓形成。我们报告，一种前列环素受体变体（R212C）在患者血液和体外COS-1过表达系统中均存在腺苷酸环化酶激活缺陷。这会促进血小板聚集增加，这是动脉粥样硬化血栓形成的一个标志。我们对3个不同白人队列中的患者进行分析发现，这种功能失调的受体不太可能是心血管疾病的起始因素，但它会加速那些具有最大风险因素的患者的疾病进程。R（212C）仅在高心血管风险队列（n = 980）中与心血管疾病相关，在低风险队列（n = 2293）中无关联。在心血管风险最高的人群中，与年龄和风险因素匹配的正常等位基因患者相比，R（212C）患者的疾病严重程度和不良心血管事件均显著增加。我们得出结论，对于单倍体不足的突变体，如R（212C），增强的动脉粥样硬化血栓形成表型可能取决于现有动脉粥样硬化或损伤（高风险因素）的存在，这与在环氧化酶-2抑制研究或前列环素受体基因敲除小鼠研究中观察到的情况类似。结合生化和临床方法，我们得出结论，前列环素受体信号传导减弱可能部分导致了环氧化酶-2抑制所观察到的潜在不良心血管结局。
